(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
23 October 2003 (23.10.2003)
PCT
in
(10) International Publication Number
WO 03/086324 A2
(51) International Patent Classification 7 :
A61K
(21) International Application Number: PCT/US03/09818
(22) International Filing Date: 2 April 2003 (02.04.2003)
(25) Filing Language:
(26) Publication Language:
(30) Priority Data:
10/120,848
English
English
10 April 2002 (10.04.2002) US
(71) Applicant: ALLOS THERAPEUTICS, INC. [US/US];
11080 CirclePoint Road, Suite 200, Westminster, CO
80020 (US).
(72) Inventors: JOHNSON, Douglas, Giles; 6244 Devinney
Circle, Arvada, CO 80004 (US). DOTY, Mark; 610 Ke-
nilworth St., Grayslake, IL 60030 (US). KIPP, James, E.;
609 Hermosa Avenue, Wauconda, IL 60084 (US).
(74) Agents: SWANSON, Barry, J. et aL; Swanson &
Bratschun, L.L.C., Suite 330, 1745 Shea Center Drive,
Highlands Ranch, CO 80129 (US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NI, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD,
SE, SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ,
VC, VN, YU, ZA, ZM, ZW.
(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
Published:
without international search report and to be republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
<
^ (54) Title: PREPARATION AND USE OF A STABLE FORMULATION OF ALLOSTERIC EFFECTOR COMPOUNDS
o
o
(57) Abstract: A pharmaceutical composition of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic
acid or its physiologically acceptable salts suitable for parenteral administration includes an aqueous formulation of 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic acid or its physiologically acceptable salt and a buffer to main-
tain the pH from about 6 to about 11. The composition in accordance with the invention reduces the amount of particulate matter
that forms in solution after heat sterilization. The invention also includes a process for making a pharmaceutical composition of
2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic acid or its physiologically acceptable salt that has
a shelf life in excess of thirty days and is useful in parental administration.
WO 03/086324
PCT/US03/09818
PREPARATION AND USE OF A STABLE FORMULATION OF
ALLOSTERIC EFFECTOR COMPOUNDS
Field of the Invention
5 The present invention is directed to a pharmaceutical preparation of allosteric effector
compounds or their physiologically acceptable salts. More particularly, the invention
includes a stable composition of 2-[4-[2-[(3 5 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-
2-methyl-propionic acid or its physiologically acceptably salt.
Background of the Invention
1 0 It has been found that a family of compounds including the specific compound 2-[4-
[2-[(3 3 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid are allosteric
modifiers of hemoglobin. This property is useful in vitro and in vivo in methods using the
compounds for allosterically modifying hemoglobin, for storing blood, for treating blood
such that the hemoglobin in said blood is allosterically modified towards a low oxygen
1 5 affinity state, and for restoring the oxygen affinity of red blood cells.
The ability to allosterically modify hemoglobin also allows the compounds to be
useful in treating a variety of disorders and conditions mediated through allosterically
modifying hemoglobin to shift oxygen equilibrium in favor of free oxygen. Such disorders
may include, but are not limited to, whole body or tissue hypothermia, hypoxia or
2 ^0 hypotension, wounds, brain injury, diabetic ulcers, chronic leg ulcers, pressure sores, tissue
transplants, stroke or cerebro ischemia, ischemia or oxygen deprivation, respiratory disorders
including acute respiratory distress syndrome and chronic obstructive pulmonary disorder,
surgical blood loss, sepsis, multi-system organ failure, normovolemic hemodilution
procedures, carbon monoxide poisoning, bypass surgery, carcinogenic tumors, oxygen
2 5 deprivation of a fetus. The compound is useful in a method comprising the step of
administering to a patient suffering from or undergoing the claimed condition a sufficient
quantity of an allosteric effector compound. In the case of carcinogenic tumors, the
compounds are useful alone, and as radiosensitizers in conjuction with ionizing radiation.
The allosteric modification properties also allow it to be useful in certain imaging methods,
3 0 especially blood oxygen level dependent MRI, and also in diagnostic methods, including
determination of tumor oxygenation, and determination of an optimal time for commencing
radiation treatment based on tumor oxygenation. The preparation and uses for 2- [4- [2- [(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid and its physiologically
WO 03/086324 PCT/US03/09818
2
acceptable salts has been described previously in U.S. Patent Numbers 5,049,695; 5,122,539;
5,290,803; 5,432,191; 5,525,630; 5,648,375; 5,661,182; 5,677,330; 5,705,521; 5,872,888;
and 5,927,283, and pending U.S. Patent Application Serial No. 10/082,130, filed February
25, 2002. These patents also describe the preparation and use of structurally similar
5 compounds. Other patents describing closely related compounds include 5,248,785;
5,731,454. These patents, applications, and all other patents, applications, and publications
referred to herein, including the USP 25 <788>, are specifically incorporated by reference
herein. As used herein, [2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-
propionic acid and its physiologically acceptably salts will be collectively referred to as an
10 "allosteric modifying compound." The most convenient form of the allosteric modifying
compound for intravenous injection, continuous infusion, or other parenteral routes is one
that is sterile and ready to administer without any mixing, admixing, filtering, or other steps.
Summary of the Invention
The present invention provides stabilized pharmaceutical compositions comprising an
1 5 allosteric modifier compound and a stabilizing compound.
The allosteric effector compounds useful in the invention are,
a compound having the formula:
R5 Re
where R1-5 may be hydrogen, halogen, or a substituted or unsubstituted C1-3 alkyl
20 group and may be the same or different,
R6-7 may each be hydrogen or methyl and may be the same or different, and
R 8 may be hydrogen, a substituted or unsubstituted C1-3 alkyl group, or a salt cation,
and
X and Z are CH 2 , NH, or O;
25 a compound having the formula:
WO 03/086324 PCT/US03/09818
3
where X and Z may each be CH 2 , CO, NH or O, and Y may be CO or NH, which the
caveat that X, Y, and Z must all be different from each other, and
R 2 -6 can be the hydrogen, halogen, substituted or unsubstituted C1.3 alkyl groups, and
may be the same or different,
R 7 . 8 can be hydrogens, methyls, ethyls, or alkyl groups in a ring connecting the two,
and
R9 can be a hydrogen, lower alkyl, or salt cation;
a compound having the formula:
R 1 = O— C— COOR9
R 8
Re °
where R 3 - 6 can be the hydrogen, halogen, substituted or unsubstituted C1-3 alkyl
group, or a C1.3 ether or ester, and these moieties may be the same or different, or alkyl
moieties of an aromatic or aliphatic ring incorporating two of the R3-6,
Ri can be connected to any position on the phenyl ring, and
sites R7-8 can be hydrogen, halogen, methyl, ethyl, and these moieties may be the
same or different, or alkyl groups in a ring connecting the two, and
R 9 can be a hydrogen, halogen, C1.3 lower alkyl, or salt cation;
a compound having the formula:
R 1 = O— C— COORg
where Ri can be connected to any position on the phenyl ring, and '
sites R7-8 can be hydrogen, halogen, methyl, ethyl, and these moieties may be the
same or different, or alkyl groups in a ring connecting the two, and
R 2 is defined as a substituted or unsubstituted aromatic compound, a substituted or
unsubstituted alkyl ring compound, or a substituted or unsubstituted phthalimide compound,
X is a carboxyl,
Y is a nitrogen,
and R2 completes the phthalimide compound by being bonded to both X and Y; and
WO 03/086324
PCT/US03/09818
where X, Y, and Z, may either be CH 2 , NH 5 O, or N, with the caveat that each are different
from the other;
a compound having the formula:
R 2
R
R4- ^R 6 "CT "COOR 9
*
where R 2 , R3, Ri ? Rs, and R 6 may be hydrogen, halogen, or alkyl groups and may be
the same or different,
R 7 and Rg may be hydrogen or methyl groups and may be the same or different, and
where the R9 moiety is hydrogen or a salt cation;
a compound having the formula:
R, = O
?3
c-
I
R4
o
c— OR 5
where R 2 is a substituted or unsubstituted aromatic compound, or a substituted or
unsubstituted aikyl ring compound, or a substituted or unsubstituted phthalimide compound
that incorporates X and Y,
*
X is a carbonyl,
Y is a nitrogen, and
R 2 completes the phthalimide compound by being bonded to both X and Y, and where
X, Y, and Z are CH 2 , NH, S, S0 2 , CO, O or N with the caveat that X, Y, and Z are each
different from one another, and
where Ri can be connected to any position on the phenyl ring, and
R 3 and R4 are hydrogen, halogen, methyl, ethyl, propyl, isopropyl, neopentyl, butyl, or
substituted or unsubstituted aryl groups and these moieties may be the same or different, or
alkyl moieties as part of an aliphatic ring connecting R3 and R4, and
R 5 is a hydrogen, halogen, C1-3 lower alkyl, or a salt cation;
a compound having the formula:
WO 03/086324
PCT/US03/09818
5
6
R 8
where A is a chemical bridge which includes two to four chemical moieties bonded
together,
the chemical moieties in A are selected from the group consisting of CO, O, S, SO2,
NH, NR9 where R 9 is a C1-6 alkyl group, CH 2 , CH, and C, with the proviso that, except in the
case where A contains two identical CH and C moieties positioned adjacent one another to
form an alkene or alkyne, the chemical moieties in A are each different from one another, and
at least one of R1-5 is substituted with a compound having the chemical formula:
where n is zero to five,
where Rio and Rn are selected from the group consisting of hydrogen, halogen, C1-12
alkyl groups, carboxylic acids and esters, aromatic or heteroatomic groups, and these
moieties may be the same or different, or alkyl moieties of part of an aliphatic ring
connecting R i0 and Rn, and where R12 is a hydrogen, halogen, salt cation, metal, or Cue alkyl
group, and
wherein a remainder of the R1.5 moieties and the Re-s moieties are selected from the group
consisting of hydrogen, halogen, Cue alkyl groups, Ci. 6 ether or esters, aromatics and
heteroaromatics, and alkyl moieties of an aliphatic ring connecting two sites on a phenyl
group;
O— (CH 2 )— C— COOR 12
WO 03/086324 PCT/US03/09818
6
a compound having the formula:
Ri — A — R 2
where Ri and R2 each are a substituted or unsubstituted aromatic or hetero aromatic
compounds, or a substituted or unsubstituted alkyl or heteroalkyl ring compound, or a
substituted or unsubstituted phthalimide compound, and
where Ri and R2 may be the same or different,
where A is a chemical bridge which includes three chemical moieties bonded together
between Ri and R2,
wherein the chemical moieties in A are selected from the group consisting of CO, O,
S, S0 2 , NH, NR 3 where R 3 is Cue alkyl group, NR4 where R4 includes two carbonyls as part
of a phthalimide compound formed with Ri or R2, CH 2 , CH, and C, and
*
where at least one of Ri and R2 is substituted with a compounds having the chemical
formula:
f 5
O— (CH 2 ) n — C— COOR 7
Re
where n is zero to five, where R 5 and Re are selected from the group consisting of
hydrogen, halogen, substituted or unsubstituted C1.12 alkyl groups, carboxylic acid and ester
groups, substituted or unsubstituted aromatic or heteroaromatic groups, and these moieties
1
may be the same or different, or alkyl moieties of part of an aliphatic ring connecting R5 and
R$, and
where R 7 is a hydrogen, halogen, salt cation, metal, or substituted or unsubstituted Ci.
6 alkyl group;
a compound having the formula:
Ri — A — R 2
where Ri and R2 each are a substituted or unsubstituted aromatic or heteroaromatic
compound, or substituted or unsubstituted alkyl or heteroalkyl ring compound, or a
substituted or unsubstituted phthalimide compound, and
where Ri and R 2 may be the same or different,
where A is a chemical bridge which includes two to four chemical moieties bonded
together between Ri and R2,
wherein said chemical moieties in A are selected from the group consisting of CO, O,
S, S0 2? NH, NR 3 where R 3 is a C1-6 alkyl group, NR4 where R4 includes two carbonyls as part
WO 03/086324
PCT/US03/09818
7
of a phthalimide compound formed with Ri or R 2 , CH 2 , CH, and C, with the caveat that,
except in the case where A contains two identical CH and C moieties positioned adjacent one
another to form an alkene or alkyne, the chemical moieties in A are each different from one
another, and
wherein at least one of Ri or R 2 is substituted with a compound having the chemical
formula:
where n is zero to five,
where R5 and Re are selected from the group consisting of hydrogen, halogen,
substituted or unsubstituted C1-12 alkyl groups, carboxylic acid and ester, substituted or
unsubstituted aromatic or heteroaromatic groups, and these moieties may be the same or
different, or alkyl moieties of part of an aliphatic ring connecting R5 and Re, and
where R7 is a hydrogen, halogen, salt cation, metal, or substituted or unsubstituted Ci_
6 alkyl group; and/or
a compound having the formula:
where Ri is selected from the group consisting of optionally substituted phenyl,
adamantyl, napthyl, and indanyl, R2-3 are alkyl moieties of a C 3 . 6 alkyl ring connecting R 2 and
R 3 , and R4 is a hydrogen, a monovalent salt cation, or a C1-3 lower alkyl.
In some embodiments, the allosteric effector compound is 2-[4-(((3,5~
dimethylanilino)carbonyl)methyl)phenoxy]-2-methylpropionic acid, or a physiologically
acceptable salt thereof.
In preferred embodiments, the allosteric effector compound is 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid or at least one
physiologically acceptable salt of 2- [4- [2 - [(3 ,5 -dimethy lpheny 1) amino] -2-oxoethyl] phenoxy] -
2-methyl-propionic acid.
25 <788>, not more than 3 particles per milliliter of particles > 25 |~im and not more than 25
O— (CH 2 ) n — C— COOR 7
Re
In some embodiments, the composition has, as measured by light obscuration per USP
WO 03/086324 PCT/US03/09818
8
particles per milliliter of particles > 1 0 |~im, while in other embodiments, the composition has,
as measured by light obscuration per USP 25 <788>, not more than 600 particles per
container of particles > 25 pm , or not more than 6000 particles per container of particles >
10 jam.
5 Preferably, the composition includes an amount of allosteric effector compound from
about 15 millimoles/L to about 120 millimoles/L.
The stabilizing agent is selected from the group consisting of orthophosphoric acid,
physiologically acceptable salts of orthophosphoric acid, citric acid, physiologically
acceptable salts of citric acid, tromethamine, meglumine, amino acids, di-peptides, tri-
10 peptides, glycine, lysine, arginine, glycyl-glycine, and combinations thereof.
The allosteric effector compound is present as a physiologically acceptable salt
selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, and
combinations thereof, in some embodiments. In further embodiments, the physiologically
acceptable salt is a salt of a compound containing an amine group. In other embodiments, the
15 compound containing a free amino group is selected from the group consisting of lysine,
hydroxy-lysine, histidine, arginine, ornithine, protonated tromethamine, meglumine, and
combinations thereof.
The composition contains an amount of 2- [4- [2- [(3 , 5 -dimethy lpheny l)amino] -2-
oxoethyl]phenoxy]-2-methyl-propionic acid effective for the treatment of conditions
20 mediated through allosterically modifying hemoglobin to shift oxygen equilibrium in favor of
free oxygen. In some embodiments, the physiologically acceptable salt of the allosteric
effector compound comprises a counter ion, which acts as the stabilizing agent.
In some embodiments, the composition is sterile. In other embodiments, the
composition comprises a diluent such as water, a saline solution, a dextrose solution, lactated
25 Ringer's solution, an aqueous solution of mannitol, or combinations thereof.
The present invention also provides a process of making a pharmaceutical
composition of an allosteric effector compound, comprising the steps of combining allosteric
effector compound or at least one physiologically acceptable salt thereof and a stabilizing
agent. In some embodiments, the allosteric effector compound is provided in a diluent, and
30 in further embodiments, the diluent has a pH above about 6.6.
In some embodiments, the stabilizing agent is added in amount sufficient to minimize
the formation of particulates in the pharmaceutical composition, for example, maintaining the
composition having not more than 3 particles per milliliter of particles > 25 \xm and not more
WO 03/086324 PCT/US03/09818
9
than 25 particles per milliliter of particles > 1 0 [im; or maintaining the composition having
not more than 600 particles per container of particles > 25 |ixm and not more than 6000
particles per container of particles > 1 0 \xm.
In some embodiments the stabilizing agent maintains the pH of the composition from
5 about 6.5 to about 1 1 . In other embodiments, the allosteric effector compound is added in an
amount ranging from about 15 millimoles/L to about 120 millimoles/L.
In other embodiments, the counterions and stabilizing agents used are those described
for the stabilized compositions of the invention.
In some embodiments, the method further provides for sterilizing the composition, for
1 0 example, by heat sterilization, by sterile filling the composition into a sterile container.
Detailed Description o f the Invention
The present invention includes pharmaceutically stabilized compositions of allosteric
15 effector compounds. As used herein, "pharmaceutically stabilized allosteric effector
compounds' 9 refers to allosteric effector compounds maintained without the formation of
substantial particulate matter. As used herein, lack of formation of substantial particulate
matter, or minimization of formation of particulate matter refers to a level of particulate
matter that makes the compound suitable for parenteral administration as defined in the
20 United States Pharmacopeia monograph <788> (USP <788>). (United States Pharmacopeial
Convention Committee of Revision, The United States Pharmacopeia, (25th edition)). This
stabilization may be effected by the addition of one or more agents which, together with the
allosteric effector compound, provide a pharmaceutical formulation which is capable of
delivering the allosteric effector compound. In some embodiments the pharmaceutically
25 stabilized composition includes a diluent in which the composition is prepared, or into which
the composition is added.
Allosteric effector compounds which may be used in the formulations of the present
invention fall into a number of different categories:
Group I: 2-[4-((aryl)acetamido)phenoxy]2-methyl propionic acid compounds having
30 the general structural formula:
O CH 3
R N ' CH 3
CH 2 -C — NH-<\ /> O— C — COOH
WO 03/086324 PCT/US03/09818
10
group II: 2-[4-(((aryl)oxy)carbonyl)amino) phenoxy]-2-methyl propionic acid compounds
having the general structural formula
O , CH 3
sx // O— C— NH
group III: 2- [4 ((((aryl)amino)carbonyl) methyl)phenoxy]-2-methyl propionic acid
compounds having the general structural formulae
O , , CH 3
II
^ h NH-C— CH 2 -4 h O
COOH
CH
and
R 7
— COOH
R
8
group IV: 2-[4-"-(((aryl)oxy)carbonyl)amino)phenoxy]-2-methyl propionic acid compounds
having the general structural formula
0 /=N pH 3
O— C — NH-<\ /) O— C — COOH
R N / CH 3
In one subset of compounds defined by the formula
R3 R 2
R 7
X and Z may each be CO or CH 2 , with the caveat that when X is CO, Z is CH 2 , and when X
is CH 2 , Z is CO. This subset of compounds may be conveniently divided into two additional
1
groupings as follows:
Group V: 2-[4-(((aryloyl)amino) methyl)phenoxy]-2-methyl propionic acid
compounds having the general structural formula
WO 03/086324 PCT/US03/09818
11
CH 3
I
O— C — COOH
CH 3
Group VI: 2-[4-((((aryl)methyl)amino) carbonyl)phenoxy] -2-methyl propionic acid
compounds having the general structural formula; and
R3 ,Ri
R-
COOR
8
R
6
Group VII has the general structural formula:
R 3 O
R
4
N
R
o
5
The image enhancing agents of the present invention are capable of allosterically
effecting hemoglobin to cause a change in the oxy-/deoxy- hemoglobin ratio. Allosteric
effector compounds useful in the present invention include compounds disclosed in U.S.
10 Patent No. 5,049,695, including
R3 ,Ri
R-
O— C— COOR 8
I
Re
where Ri_ 5 may be hydrogen, halogen, or a substituted or unsubstituted C1-3 alkyl group and
may be the same or different, wherein R^i may each be hydrogen or methyl and may be the
same or different, and wherein Rg may be hydrogen, a substituted or unsubstituted C1-3 alkyl
15 group, or a salt cation, and where X and Z are CH 2 , NH, or O. Other allosteric effector
compounds useful in the present invention disclosed in U.S. Patent No. 5,122,539 include
WO 03/086324 PCT/US03/09818
12
where X and Z may each be CH 2 , CO, NH or O, and Y may be CO or NH, which the caveat
that X, Y, and Z must all be different from each other. R 2 -6 can be the hydrogen, halogen,
substituted or unsubstituted C1-3 alkyl groups, and may be the same or different, R 7 -g can be
5 hydrogens, methyls, ethyls, or alkyl groups in a ring connecting the two, and R9 can be a
hydrogen, lower alkyl, or salt cation.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,248,785 and U.S. Patent No. 5,250,701, including
10 where R3-6 can be the hydrogen, halogen, substituted or unsubstituted C1-3 alkyl group, or a
C1-3 ether or ester, and these moieties may be the same or different, or alkyl moieties of an
aromatic or aliphatic ring incorporating two of the R3-6, and where Ri can be connected to
any position on the phenyl ring, and sites R 7 -g can be hydrogen, halogen, methyl, ethyl, and
these moieties may be the same or different, or alkyl groups in a ring connecting the two, and
15 R9 can be a hydrogen, halogen, C1-3 lower alkyl, or salt cation.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,290,803 including
f
where Ri is a tail structure as defined above in connection with U.S. Patent 5,248,785, and R2
20 is defined as a substituted or unsubstituted aromatic compound, a substituted or unsubstituted
alkyl ring compound, or a substituted or unsubstituted phthalimide compound X is a
carboxyl, Y is a nitrogen and R2 completes the phthalimide compound by being bonded to
WO 03/086324
PCT/US03/09818
13
both X and Y; and where X, Y, and Z, may either be CH 2 , NH, O, or N, with the caveat that
each are different from the other.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5, 382,680 including
wherein the R 2 , R3, R4, Rs, and R 6 moieties may be hydrogen, halogen, or alkyl
groups and may be the same or different, wherein the R 7 and R 8 moieties may be hydrogen or
methyl groups and may be the same or different, and wherein the R9 moiety is hydrogen or a
salt cation.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,432,191 including
R1 = O
I 3 II
c— c-
I
OR,
where R2 is a substituted or unsubstituted aromatic compound, or a substituted or
unsubstituted alkyl ring compound, or a substituted or unsubstituted phthalimide compound
that incorporates X and Y where X is a carbonyl, Y is a nitrogen and R 2 completes the
phthalimide compound by being bonded to both X and Y, and where X, Y, and Z are CH 2 ,
NH, S, S0 2 , CO, O or N with the caveat that the X, Y, and Z moieties are each different from
one another, and where Ri can be connected to any position on the phenyl ring, and R3 and R4
are hydrogen, halogen, methyl, ethyl, propyl, isopropyl, neopentyl, butyl, or substituted or
unsubstituted aryl groups and these moieties may be the same or different, or alkyl moieties
as part of an aliphatic ring connecting R 3 and R4, and R 5 is a hydrogen, halogen, C1-3 lower
alkyl, or a salt cation.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,591,892* including
WO 03/086324
14
PCT/US03/09818
where A is a chemical bridge which includes two to four chemical moieties bonded together,
wherein the chemical moieties in A are selected from the group consisting of CO, O, S, S0 2 ,
i
NH, NR 9 where R 9 is a Ci. 6 alkyl group, CH 2 , CH, and C, with the proviso that, except in the
case where A contains two identical CH and C moieties positioned adjacent one another to
form an alkene or alkyne, the chemical moieties in A are each different from one another, and
wherein at least one of R1.5 is substituted with a compound having the chemical formula:
1
O— (CH 2 ) n — C— COOR 12
R 11
1
where n is zero to five, where Rio and Rn are selected from the group consisting of hydrogen,
10 halogen, Ci_i 2 alkyl groups, carboxylic acids and esters, aromatic or heteroatomic groups, and
these moieties may be the same or different, or alkyl moieties of part of an aliphatic ring
connecting Rio and Rn, and where R12 is a hydrogen, halogen, salt cation, metal, or Ci- 6 alkyl
group, and wherein a remainder of the R1-5 moieties and the R6-8 moieties are selected from
the group consisting of hydrogen, halogen, Ci- 6 alkyl groups, C1-6 ether or esters, aromatics
1 5 and heteroaromatics, and alkyl moieties of an aliphatic ring connecting two sites on a phenyl
group.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,648,375 including a compound of the formula
R { — A — R 2 where Ri and R 2 each are a substituted or unsubstituted aromatic or
20 heteroaromatic compounds, or a substituted or unsubstituted alkyl or heteroalkyl ring
compound, or a substituted or unsubstituted phthalimide compound, and where Ri and R 2
may be the same or different, where A is a chemical bridge which includes 3 chemical
moieties bonded together between R x and R 2 , wherein the chemical moieties in A are selected
from the group consisting of CO, O, S, S0 2 , NH, NR 3 where R 3 is Ci_ 6 alkyl group, NR4
25 where R4 includes two carbonyls as part of a phthalimide compound formed with Ri or R 2 ,
CH 2 , CH, and C, and where at least one of Ri and R 2 is substituted with a compounds having
the chemical formula:
WO 03/086324 PCT/US03/09818
15
O— (CH 2 ) n — C— COOR 7
Rq
where n is zero to five, where R 5 and R 6 are selected from the group consisting of hydrogen,
halogen, substituted or unsubstituted C1-12 alkyl groups, carboxylic acid and ester groups,
substituted or unsubstituted aromatic or heteroaromatic groups, and these moieties may be the
5 same or different, or alkyl moieties of part of an aliphatic ring connecting R 5 and R6, and
where R 7 is a hydrogen, halogen, salt cation, metal, or substituted or unsubstituted Ci_ 6 alkyl
group.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,661,182, including an allosteric effector molecule
10 which (i) binds to only one pair of symmetry related sites in the central water cavity of
hemoglobin at the Lys 99 a, Arg 141 a, and Asn 108 IS residues, each pair of symmetry
related sites having residues on three separate sub-units of the hemoglobin, (ii) stabilizes the
hemoglobin in a lower oxygen affinity state, and (iii) is active in the presence of normal
concentrations of serum albumin in the blood, the allosteric effector molecule (a) maintains
1 5 greater than sixty percent of its activity in terms of right shifting the oxygen dissociation
curve of hemoglobin for a buffered red ceil suspension at pH 7.4, in 140 mM NaCl and 50
mM bis-Tris buffer at 37° C, which contains 20-25 |uM hemoglobin on a tetramer basis, 50
jaM serum albumin, and 0.5 mM of the allosteric effector molecule, relative to the buffered
red cell suspension without 50 |uM serum albumin, and (b) maintains greater than eighty
20 percent of its activity in terms of a calculated oxygen delivery index for the buffered red cell
suspension containing 50 |aM serum albumin relative to the buffered red cell suspension
without 50 |LiM serum albumin; and permitting the allosteric effector molecule to penetrate
into erythrocytes in the blood and bind to the hemoglobin therein.
Also included as allosteric effector compounds useful in the present invention are
25 compounds disclosed in U.S. Patent Nos. 5,677,330, 5,705,521 and 5,927,283 including a
compound of the formula Ri — A — R 2 where Ri and R 2 each are a substituted or unsubstituted
aromatic or heteroaromatic compound, or substituted or unsubstituted alkyl or heteroalkyl
ring compound, or a substituted or unsubstituted phthalimide compound, and where Ri and
R 2 may be the same or different, where A is a chemical bridge which includes two to four
30 chemical moieties bonded together between Ri and R 2 , wherein said chemical moieties in A
are selected from the group consisting of CO, O, S, S0 2 , NH, NR 3 where R 3 is a Ci_ 6 alkyl
WO 03/086324
PCT/US03/09818
16
10
group, NR4 where R4 includes two carbonyls as part of a phthalimide compound formed with
Ri or R 2 , CH 2 , CH 5 and C, with the caveat that, except in the case where A contains two
identical CH and C moieties positioned adjacent one another to form an alkene or alkyne, the
chemical moieties in A are each different from one another, and wherein at least one of Ri or
R 2 is substituted with a compound having the chemical formula:
O— (CH 2 ) n — C— COOR 7
Re
where n is zero to five, where . R 5 and R6 are selected from the group consisting of hydrogen,
halogen, substituted or unsubstituted C1-12 alkyl groups, carboxylic acid and ester, substituted
or unsubstituted aromatic or heteroaromatic groups, and these moieties may be the same or
different, or alkyl moieties of part of an aliphatic ring connecting R 5 and Re, and where R 7 is
a hydrogen, halogen, salt cation, metal, or substituted or unsubstituted C1-6 alkyl group.
Also included as allosteric effector compounds useful in the present invention are
compounds disclosed in U.S. Patent No. 5,73 1,454 including
M O H
c— c-
OR
1 5 where Ri is selected from the group consisting of optionally substituted phenyl, adamantyl,
napthyl, and indanyl, R2-3 are alkyl moieties of a C3-6 alkyl ring connecting R 2 and R 3 , and R4
is a hydrogen, a monovalent salt cation, or a C1-3 lower alkyl. Each of the above named
patents, and all other patents and publications referred to herein, are incorporated by
reference herein in their entirety.
20 In a preferred embodiment, the allosteric effector compound is 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid, which has the
following structure:
CH 3 O
OH
H3C CH3
!
WO 03/086324
PCT/US03/09818
17
The sodium salt of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-
methyl-propionic acid (C 2 oH 2 2N04Na; Molecular Weight = 363.38) has the following
structure:
ONa
H3C CH3
These compounds may be used in the composition in its acid form or in the form of a
physiologically acceptable salt. The physiologically acceptable salt of 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid can be represented as
having the following general structure where X + represents the cation of the physiologically
acceptable salt:
CH 3 O
H3C CH3
The salt may include compounds with inorganic or organic cationic counterions. For
example, inorganic counterions may include, but are not limited to, sodium, potassium,
calcium, magnesium, zinc, and combinations thereof. Organic counterions may include, but
are not limited to, lysine, hydroxy-lysine, histidine, arginine, ornithine, tromethamine,
meglumine, and combinations thereof.
The allosteric modifying compound is preferably placed in solution prior to
administration. The solution may be made using water, a saline solution, a dextrose solution,
a lactated Ringer's solution, an aqueous solution of mannitol, or combinations thereof as the
diluent. Other diluents may be used as long as they are suitable for parenteral administration
«
to a patient. Preferably, the diluent does not reduce the chemical or physical (particle)
stability of the allosteric modifying compound such that it fails the (USP) 25
<78 8>requirement.
Parenteral products must meet certain requirements for subvisual particulate matter.
Failure to meet these requirements may result in the product being unacceptable for
therapeutic treatment. The USP <788> provides standards for determining subvisual
WO 03/086324 PCT/US03/09818
18
particulate matter. Two tests are provided, a light obscuration particle count test, and a
microscopic particle count test. If the injection fails the light obscuration test, then it must
pass the microscopic procedure. Alternatively, if a preparation can not be tested by light
obscuration for technical reasons, e.g., high viscosity, microscopic testing can be used
5 exclusively. For small volume injections of not more than 100 ml, the USP 25 <788> light
obscuration limit for particles > 10 microns is not more than 6000 per vial and for particles >
25 microns the limit is not more than 600 per vial. For large volume injections, greater than
100 ml, the USP 25 <788> light obscuration limit for > 10 micron particles is not more than
25 per ml and the limit for 25 micron particles is not more than 3 per ml. Thus, in some
] 1 0 embodiments, the size of the container determines the total number of particles that may be
present. For example, for a 100 mL container (defined by the USP as a small volume
injectable) , the requirement is 6 particles per milliliter of particles larger than > 25 p,m and
not more than 60 particles per milliliter of particles > 10 |um.
For small volume injections of not more than 100 ml, the microscopic limit for
15 particles > 10 microns is 3000 per vial. The USP 25 microscopic limit for particles > 25
microns for small volume injections is 300 per vial. For larger volume injections, greater
than 100 ml, the USP 24 microscopic limit for > 10 micron particles is not more than 12 per
ml and the limit for > 25 micron particles is not more than 2 per ml.
In one embodiment where the composition will be used for treating conditions
; 20 mediated through allosterically modifying hemoglobin, the composition preferably contains
an amount of the allosteric modifying compound that is effective for allosterically modifying
hemoglobin.
Preferably, the composition of the present invention comprises an amount ranging
from about 15 millimoles/L to about 150 millimoles/L of the allosteric modifying compound.
25 More preferably, the amount ranges from about 45 millimoles/L to about 90 millimoles/L of
the allosteric modifying compound. In the most preferred embodiments, the composition of
the present invention comprises about 58.7 mmol/L of the allosteric modifying compound.
The amount of the allosteric modifying compound added can vary and depends on factors
known to one skilled in the art. Factors may include the condition to be treated as well as the
30 size and health of the patient.
It has been found that a formulation of the allosteric effector compound 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid at 20 mg/mL (58.7
mmol/L) at pH 7.5, not including a stabilizing compound, that was heat sterilized developed a
WO 03/086324 PCT/US03/09818
19
precipitate of the allosteric modifier within one week after sterilization. While the allosteric
modifying compound in this composition was stable to chemical degradation, this formation
of particulate matter may result in the preparation failing the USP requirements.
Interestingly, the formation of particulate matter takes place even though the cqncentration of
5 the allosteric modifying compound is less than half of the solubility limit for the compound at
the pH of the solution. The pKa for 2-[4-[2-[(3 ? 5-dimethylphenyl)amino]-2- ,
oxoethyl]phenoxy]-2-methyl-propionic acid is about 3.5. Accordingly, there is an
appreciable solubility at a pH of 7. The solubility of the sodium salt of 2- [4- [2- [(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid at apH of 7 is about
10 50 mg/ml. Surprisingly, 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-
methyl-propionic acid begins to precipitate out of solution, forming subvisual particulate
where the concentration of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-
i
methyl-propionic acid is only 20 mg/ml and the pH of the solution is about 7 at 25°C. Not
being limited by this theory, these solubility studies suggest that this compound may be
1 5 surface active, and undergoing a phase transition from a monomeric form to some sort of
associated species, such as a small aggregate, oligomer or micelle, which solubilizes traces of
the unionized acid. It is thought that the addition of a stabilizing agent maintains the integrity
of this small aggregate-like species.
This unforeseen problem of formation of particulate matter at concentrations beneath
20 the solubility of the compound is solved by the addition of a stabilizing agent. The effect of
the stabilizing agent is to prevent or minimize the formation of sub- visual particulates. In
some embodiments, the stabilizing agent may also act as a buffer to stabilize the pH of the
solution. In other embodiments, the stabilizing agent and buffering agent are different. The
stabilizing agent acts to prevent the formation of significant amounts of sub-visual particulate
25 matter, particularly after heat sterilization. The result is a formulation that can be terminally
sterilized, have a long shelf life, and meet the USP 25 <788> sub-visual particulate matter
requirements. Without being bound by theory, it is believed that stabilization of pH is one
factor contributing to stabilization of the formulation; however, the pH of the solution alone
is insufficient to stabilize the solutions. Studies have shown that the pH of the allosteric
30 effector compound should be greater than about 6.6 for optimum solubility. If necessary, the
pH of the solution can be adjusted to a pH of at least about 6, preferably from about 6 to
about 11. More preferably, the pH is adjusted to about 6.5 to about 9.0. More preferably, the
pH is adjusted to about 7.5 to 8.5. The pH may be adjusted by the addition of any appropriate
acid or base. Suitable acids may be amino acids, carboxylic acids, phosphoric acid,
WO 03/086324 PCT/US03/09818
20
hydrochloric acid or other acids suitable for pharmaceutical preparations. Suitable bases
include, sodium hydroxide or other bases suitable for pharmaceutical preparations.
The composition of the present invention includes a stabilizing agent. The stabilizing
agent may minimize pH drift, but more importantly, the stabilizing agent acts to inhibit the
5 formation of particulate matter in the composition. The stabilizing agent may be added to the
composition as an additional component or, where the counter ion of a physiologically
acceptable salt of the allosteric modifying compound being used has the capacity to act as a
stabilizing agent, the counter ion itself may serve as the stabilizing agent. Without being
bound by theory, one possible mechanism that allows the stabilizing agent to prevent
1 0 particulate formation is that the stabilizing agent acts as a proton "sink" that lowers the
probability of the formation of the less soluble neutral protonated allosteric modifier.
The selection of the stabilizing agent may depend, in part, on the final pH desired.
The amount of the stabilizing agent will vary depending upon several factors known to those
skilled in the art. Some of these factors include the composition of the stabilizing agent, the
1 5 pKa(s) of the stabilizing agent, the concentration of the allosteric modifying compound, the
amount of the solution to be stabilized, and the sterilization cycle used. The amounts and
factors may vary from one stabilizing agent to the next. In any event, the amount of the
stabilizing agent added to the composition should be an amount that is effective to reduce the
formation of particulate matter in the composition. Further, the amount of stabilizing agent
*
20 may preferably be an amount that maintains the pH of the composition within a desired
range.
Suitable stabilizing agents include, but are not limited to, orthophosphoric acid,
physiologically acceptable salts of orthophosphoric acid, citric acid, physiologically
acceptable salts of citric acid, tromethamine, meglumine, amino acids, di-peptides, tri-
25 peptides, glycine, glycyl-glycine, lysine, arginine, and other compounds containing an amine
group , and combinations thereof.
In one embodiment, the stabilizing agent is orthophosphoric acid at a concentration of
about 1-5 mM and the formulation has a pH of about 7.5, 8.0, or 8.5. In another embodiment,
the stabilizing agent is tromethamine at a concentration of about 1-5 mM and the formulation
30 has apH of about 7.5, 8.0, or 8.5.
As a result of the investigation of the unexpected precipitate in formulations of 2-[4-
[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid, it has been
discovered that the concentration of the stabilizing agent and the solubility are surprisingly
related in some cases. For example, an increase in solubility of approximately 12 mg/mL
WO 03/086324 PCT/US03/09818
21
was found in 100-200 mM meglumine solutions at 23 °C and a pH of 7.5. The solubility of
2-[4-[2-[(3 5 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid
increased steadily from approximately 44 mg/mL in water to 99.89 mg/mL in a 0.5 M tris
solution at 23 °C and a pH of 7-8. Finally, the solubility of 2-[4-[2-[(3,5-
5 dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid increased
significantly, from approximately 44 mg/mL in water to 155.07 mg/mL in a 0.5 M arginine
solution at 23 °C and a pH of 7.2-7.5. Accordingly, stabilizing agents having an amine group
are contemplated within the scope of this invention.
The composition of the present invention may be prepared by adding the allosteric
10 modifying compound to an appropriate diluent and stabilizing agent. As discussed above,
suitable diluents include, but are not limited to, water, a saline solution, a dextrose solution,
lactated Ringer's solution, an aqueous solution of mannitol, and combinations thereof.
Where the stabilizing agent is not the counter ion of a salt of the allosteric modifying
compound, the stabilizing agent is added to the solution as a separate component. The order
15 in which the stabilizing agent, the allosteric modifying compound, and the pH adjuster is
added is not critical. The stabilizing agent may be added to the liquid before or after the
addition of the allosteric modifying compound.
Once the composition is prepared, it may be filled into a container. Alternatively, the
preparation of the composition may occur in the container. Where the preparation is for
20 intravenous administration, the composition may be prepared in the intravenous bag or bottle
containing the intravenous solution.
Preferably, the composition should be sterile for administration. The preparation of
the pharmaceutical composition may be made in a sterile environment. Any sterilization
method that does not change the chemical composition of the allosteric modifying compound
25 or induce particulate formation to the point where the pharmaceutical composition would fail
the USP 24 <788>requirements may be used. Suitable methods may include, but are not
limited to, sterile filling the composition into a sterile container, filling a container with the
composition followed by heat sterilization, filter sterilization prior to filing the container;
sterile filling the composition into a sterile container and heat sterilization.
30 The stabilized formulations of the present invention are stabilized for varying time
periods. In one embodiment, the formulation is stabilized for at least about two weeks. In
another embodiment, the formulation is stabilized for at least about 30 days. In a further
embodiment, the formulation is stabilized for at least about six months. In yet a further
WO 03/086324 PCT/US03/09818
22
embodiment, the formulation is stabilized for at least about one year. In yet a further
embodiment, the formulation is stabilized for at least about two years.
The composition in accordance with the present invention has reduced particulate
matter in solution and is suitable for parenteral routes of administration, including but not
limited to, intravenous injection, continuous infusion, subcutaneous injection, intramuscular
injection, and intraperitoneal injection.
The allosteric modifying compound is chemically and physically stable between a pH
of about 6 and about 11. Preferably, the composition has a pH of at least about 6. More
preferably, the composition has a pH ranging from about 6 to about 1 1 . Most preferably, the
composition has a pH ranging from about 6.5 to about 9.0.
As illustrated in Table I, the presence of a stabilizing agent significantly reduces the
number of particles forming in the solution after terminal sterilization. All preparations were
made at a concentration that was under half of their solubility limits.
Table I: Instrumental Particulate Matter observed Immediately After Terminal Sterilization
for Four Formulations of 59 millimoles/L (20 mg/mL) 2-[4-[2-[(3,5-dimethylphenyl)amino]-
2-oxoethyl]phenoxy]-2-methyl-propionic acid in 0.225% NaCl with the following stabilizing
agents:
Stabilizing Agent
> 1 0 n (counts/mL)
> 25 u. (counts/mL)
USP Limit for Large
Volume Injectables
NMT25
NMT3
None
140
6
Phosphate
2
0
Glycyl-Glycine
4
0
Tromethamine
13
0
The composition of the present invention is chemically stable and stable with respect
L
to the formation of particulate matter for at least about thirty days. This makes the
composition particularly useful at the administration site because no additional steps, such as
filtering the composition, are necessary prior to administration to a patient. Stability data is
provided in Table II. Time is time after sterilization.
WO 03/086324
23
PCT/US03/09818
> 1 0 jo, (counts/mL)
> 25 \i (counts/mL)
USP Limit for Large
Volume Injectables
NMT 25
NMT 3
Stabilizing AgentYTime
0
6 mo.
12 mo.
0
6 mo.
12 mo.
Phosphate 1 mM
3
20
4
0
0
0
Glycyl-Glycine 1 nM
4
4
4
0
0
0
Tromethamine 1 mM
12
10
9
0
0
0
It will be readily understood by those persons skilled in the art that the present
5 invention is susceptible to broad utility and application. Many embodiments and adaptations
of the present invention other than those herein described, as well as many variations,
modifications and equivalent arrangement, will be apparent from or reasonably suggested by
the present invention and the foregoing description without departing from the substance or
i
scope of the present invention.
i.
10 The foregoing disclosure is not intended to be construed to limit the present invention
or otherwise exclude other embodiments, adaptations, variations, modifications or equivalent
arrangements, the present invention being limited only by the appended claims and their
equivalents.
WO 03/086324
What is claimed is:
24
CLAIMS
PCT/US03/09818
1 . A stabilized pharmaceutical composition comprising an allosteric modifier
5 compound and a stabilizing compound.
2. The pharmaceutical composition of Claim 1, wherein the allosteric effector
compound is 2-[4-[2-[(3 9 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic
acid or at least one physiologically acceptable salt of 2-[4-[2-[(3 5 5-dimethylphen}d)amino]-2-
1 0 oxoethyl]phenoxy] -2-methyl-propionic acid.
3. The pharmaceutical composition of Claim 1, wherein the composition has not
more than 3 particles per milliliter of particles > 25 \im and not more than 25 particles per
milliliter of particles > 1 0 pm.
15
4. The pharmaceutical composition of Claim 1, wherein the composition has not
more than 600 particles per container of particles > 25 jam and not more than 6000 particles
per containerof particles > 10 jam.
20 5. The pharmaceutical composition of Claim 1, wherein the composition has not
T
more than 2 particles per milliliter of particles > 25 |um and not more than 12 particles per
milliliter of particles > 1 0 jum.
6. The pharmaceutical composition of Claim 1, wherein the composition has not
25 more than 300 particles per container of particles > 25 jum and not more than 25 particles per
milliliter of particles > 1 0 |nm.
7. The composition of claim 2 ? comprising an amount of 2-[4-[2-[(3 5 5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy] -2-methyl-propionic acid or at least one
30 physiologically acceptable salt of 2-[4-[2-[(3 5 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-
2-methyl-propionic acid ranging from about 15 millimoles/L to about 120 millimoles/L.
WO 03/086324 PCT/US03/09818
25
8. The composition of claim 2, comprising an amount of 2-[4-[2-[(3 5 5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid or at least one
physiologically acceptable salt of 2-[4-[2-[(3 5 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-
2-methyl-propionic acid ranging from about 45 millimoles/L to about 90 millimoles/L.
5
9. The composition of claim 1 wherein the stabilizing agent is selected from the
group consisting of orthophosphoric acid, physiologically acceptable salts of orthophosphoric
acid, citric acid, physiologically acceptable salts of citric acid, tromethamine, meglumine,
amino acids, di-peptides, tri-peptides, glycine, lysine, arginine, glycyl-glycine, and
1 0 combinations thereof.
10. The composition of claim 2, wherein 2-.[4-[2-[(3,5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid is present as a physiologically acceptable salt
selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, and
1 5 combinations thereof.
1 1 . The composition of claim 2 wherein 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid is present as a physiologically acceptable salt of
a compound containing an amine group.
20
12. The composition of claim 1 1 wherein the compound containing an amine
group is selected from the group consisting of lysine, hydroxy-lysine, histidine, arginine,
ornithine, tromethamine, meglumine, and combinations thereof.
13. The composition of claim 2, comprising an amount of 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid effective for the
treatment of conditions mediated through allosterically modifying hemoglobin to shift
oxygen equilibrium in favor of free oxygen.
14. The composition of claim 1, comprising a physiologically acceptable salt of 2-
[4-[2-[(3,5-dimethylphenyl)amino]~2-oxoethyl]phenoxy]-2-methyl-propionic acid having a
counter ion, and wherein the counter ion acts as the stabilizing agent.
15. The composition of claim 1 wherein the composition is sterile.
WO 03/086324
26
PCT/US03/09818
16. The composition of claim 1, further comprising a diluent, wherein said diluent
is selected from the group consisting of water, a saline solution, a dextrose solution, lactated
Ringer's solution, an aqueous solution of mannitol, glucose polymers, modified glucose
polymers, and combinations thereof.
17. A process of making a pharmaceutical composition of 2-[4-[2-[(3 5 5-
dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid, comprising the steps
of combining 2- [4- [2- [(3 , 5 -dimethy lpheny 1) amino] -2-oxoethyl] phenoxy] -2 -methyl-propionic
acid or at least one physiologically acceptable salt of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid and a stabilizing agent.
1 8. The process of Claim 17, wherein said 2 - [4- [2- [(3 ,5 -dimethy lpheny l)amino] -
2-oxoethyl]phenoxy]-2-methyl-propionic acid or at least one physiologically acceptable salt
of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid is
provided in a diluent.
19. The process of Claim 18, wherein the diluent has a pH above about 6.6.
it. :
20. The process of Claim 17, wherein the stabilizing agent is added in amount
sufficient to minimize the formation of particulates in the pharmaceutical composition.
2 1 . The process of Claim 1 7, wherein the stabilizing agent maintains the
composition having not more than 3 particles per milliliter of particles > 25 jum and not more
than 25 particles per milliliter of particles > 10 jam.
22. The process of Claim 17, wherein the stabilizing agent maintains the
composition having not more than 6 particles per milliliter of particles > 25 \xm and not more
than 60 particles per milliliter of particles > 1 0 jam.
23. The process of claim 17 wherein the stabilizing agent maintains the pH of the
composition from about 6.5 to about 1 1 .
WO 03/086324 PCT/US03/09818
27 -
24. The process of claim 17 wherein the stabilizing agent maintains , the pH of the
composition from about 6.5 to about 9.0.
25. The process of claim 17 wherein 2-[4-[2-[(3 ? 5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid or at least one physiologically acceptable salt of
2- [4- [2- [(3 ? 5-dimethylpheny l)amino] -2-oxoethy 1] phenoxy] -2-methy 1-propionic acid is added
in an amount ranging from about 15 millimoles/L to about 120 millimoles/L.
26. The process of claim 17 wherein 2-[4-[2-[(3 5 5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid or at least one physiologically acceptable salt of
2-[4-[2-[(3 ? 5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propionic acid is added
in an amount ranging from about 45 millimoles/L to about 90 millimoles/L.
27. The process of claim 17 wherein the buffer is selected from the group
consisting of orthophosphoric acid, physiologically acceptable salts of orthophosphoric acid,
citric acid, physiologically acceptable salts of citric acid, tromethamine, meglumine, amino
acids, di-peptides, tri-peptides, glycine, lysine, arginine, glycyl-glycine, and combinations
thereof.
28. The process of claim 17 wherein 2-[4»[2-[(3,5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid is present as a physiologically acceptable salt
selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, and
combination thereof.
29. The process of claim 17 wherein 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-
oxoethyl]phenoxy]-2-methyl-propionic acid is present as a physiologically acceptable salt
selected from the group consisting of lysine, hydroxy-lysine, histidine, arginine, ornithine,
protonated tromethamine, meglumine, and combinations thereof.
30. The process of claim 17 further comprising the step of sterilizing the
composition.
3 1 . The process of claim 30 wherein the sterilizing step is performed by heat
sterilization.
WO 03/086324
28
PCT/US03/09818
32. The process of claim 17 further comprising sterile filling the composition into
a sterile container.
33. The process of claim 18 wherein the diluent is selected from the group
consisting of water, saline solution, dextrose solution, lactated Ringer's solution, an aqueous
solution of mannitol, glucose polymers, modified glucose polymers, and combinations
thereof.
34. A method of allosterically modifying hemoglobin, comprising administering to a
patient in need thereof a stabilized pharmaceutical composition of Claim 1 .
35. A method for measuring a blood oxygen level-dependent magnetic resonance
imaging signal, comprising
a) administering a stabilized pharmaceutical composition of Claim 1 ; and
b) performing a blood oxygen level-dependent magnetic resonance imaging scan,
whereby said blood oxygen level-dependent magnetic resonance imaging signal is measured.
36. A method of increasing the sensitivity of cells to the cytotoxic effects of
ionizing radiation comprising:
a) contacting the cells with stabilized pharmaceutical composition of Claim lto
ii
oxygenate the cells; and
b) administering an effective cytotoxic dose of ionizing radiation to the cells.
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
(43) International Publication Date
23 October 2003 (23.10.2003)
PCT
I
(10) International Publication Number
WO 2003/086324 A3
(51) International Patent Classification 7 : A61K 9/14,
31/40, 31/27, 31/265, 31/21, 31/235, 31/24
(21) International Application Number:
PCTYUS2003/009818
(22) International Filing Date: 2 April 2003 (02.04.2003)
(25) Filing Language:
(26) Publication Language:
(30) Priority Data:
10/120,848
English
English
1 0 April 2002 ( 1 0.04.2002) US
(71) Applicant: ALLOS THERAPEUTICS, INC. [US/US];
11080 CirclePoint Road, Suite 200, Westminster, CO
80020 (US).
(72) Inventors: JOHNSON, Douglas, Giles; 6244 Devinney
Circle, Arvada, CO 80004 (US). DOTY, Mark; 610 Ke-
nilworth St., Grayslake, IL 60030 (US). KIPP, James, E.;
609 Hermosa Avenue, Wauconda, IL 60084 (US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, EE, GB, GD, GE, GH,
GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NI, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD,
SE, SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ,
VC, VN, YU, ZA, ZM, ZW.
(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
ES, FT, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
Published:
— with international search report
— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments
(88) Date of publication of the international search report:
4 November 2004
(74) Agents: SWANSON, Barry, J. et al.; Swanson &
Bratschun, L.L.C., Suite 330, 1745 Shea Center Drive,
Highlands Ranch, CO 80129 (US).
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
m
^® (54) Title: PREPARATION AND USE OF A STABLE FORMULATION OF ALLOSTERIC EFFECTOR COMPOUNDS
(57) Abstract: A pharmaceutical composition of 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic
acid or its physiologically acceptable salts suitable for parenteral administration includes an aqueous formulation of 2-[4-[2-[(3,5-
dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic acid or its physiologically acceptable salt and a buffer to main-
tain the pH from about 6 to about 11. The composition in accordance with the invention reduces the amount of particulate matter
that forms in solution after heat sterilization. The invention also includes a process for making a pharmaceutical composition of
2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxyl]-2-methyl-proprionic acid or its physiologically acceptable salt that has
a shelf life in excess of thirty days and is useful in parental administration.
INTERNATIONAL SEARCH REPORT
International application Nn_
PCT/US03/09818
A. CLASSIFICATION OF SUBJECT MATTER
IPC(7) A61K 9/14, 31/40, 31/27, 31/265, 31/21, 31/235, 31/24
US CL 424/489, 400; 514/421, 486, 512, 513, 533, 534
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 424/489, 400; 514/421, 486, 512, 513, 533, 534
Documentation searched other than iriinimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
EAST/BRS
C. DOCUMENTS CONSI DERED TO BE RELEVANT
Category *
Citation of document, with indication, where appropriate, of the relevant passages
US 5,677,330 A (ABRAHAM et al) 14 October 1997 ( 14. 10. 1997), see entire document.
Relevant to claim No.
1-36
| | Further documents are listed in the continuation of Box C. j^] See patent family annex.
"E"
"L"
Special categories of cited documents:
document defining the general state of the art winch is not considered to he
of particular relevance
earlier application or patent published on or after the international filing date
document which may throw doubts on priority claim(s) or which is cited to
establish the publication date of another citation or other special reason (as
specified)
document referring to an oral disclosure, use, exhibition or other means
document published prior to the international filing date but later than the
priority date claimed
later document published alter the international tiling date or priority
date and not in conflict with the application but cited to understand the
principle or theory underlying the invention
document of particular relevance: the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document is taken alone
document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, .such combination
being obvious to a person skilled in the an
document member of the same patent family
Date of the actual completion of the inter national search
1 1 August 2004 ( 1 1 .08.2004)
Name and mailing address of the ISA/US
Mail Stop PCT. Attn: IS A/ US
Commissioner for Patents
P.O. Box 1450
Alexandria, Virginia 22313-1450
Facsimile No. (703) 305-3230
Date of mailing of the international search report
2 2 SEP 2004
Authorized officer
Simon J. Oh
Telephone No. (571) 272-1600
Leer
Form PCT/ISA/2I0 ( second sheet) (July 1998)